DESCRIPTION: This application studies the genetic defect in alpha-1-antitrypsin (alpha-1-AT) liver disease in children. An abnormal alpha-1-antitrypsin molecule (alpha-1-ATZ) is produced in patients and as a result of its accumulation in hepatocytes creates liver damage leading to cirrhosis and, in some cases, to cancer. The principal investigator provides preliminary data that alpha-a-ATZ is handled differently in patients who have liver disease compare to those who have the inborn genetic defect but are not susceptible to the disease. They show that alpha-1-AT is handled differently by the endoplasmic reticulum (ER) as it interacts with the molecule calnexin. In the susceptible patient developing liver disease, the molecule is retained in a complex form and the complex is retained by not broken down by conventional ER catabolism. In the protected host the abnormal molecule and it's complex are retained but are more readily broken down by proteasomes. In this application, the principal investigator and co-investigators propose to study, in greater detail, the genetic defect that results in the delayed ER degradation in several different susceptible hosts, to use family studies to determine the mode of genetic transmission in each case, to determine the structural requirements for induction of calnexin ubiquitization by alpha-1-ATZ and to examine the effect of perturbations in proteasome activity on the rate of degradation of alpha-1-ATZ. They also plan to begin long-term studies to determine the mechanism(s) by which alpha-1-ATZ in the endoplasmic reticulum on hepato cell function causes hepatic dysfunction. These studies will ultimately allow the investigators to predict susceptibility among alpha-1-AT deficient patients hosts, target-susceptible hosts for specific pharmacologic interventions and will provide new information about how the quality control apparatus of the cell, the ER, works.